Many diseases are believed to stem from somatic genetic mutation rather than inherited gene abnormalities, including different types of cancers and neurodegenerative diseases.
Diseases which are caused by somatic mutation are often age-related, with an increasing incidence of somatic mutation with increasing age. For example, the prevalence of cancer increases with age, and it appears that some cancers are caused by somatic mutation. Cancer is the second leading cause of death in the United States, accounting for approximately 500,000 deaths (or 20 percent of all deaths) per year. These diseases are so prevalent that unless current trends are reversed, one in three living Americans will develop cancer at some time. Cancers are usually detected by clinical methods and cytological methods and are difficult to detect early. In some cases, familial cancers have been traced to inherited genes, and detection of such genes is believed to be predictive of susceptibility to the cancer.
It is an object of the present invention to provide methods and assays for detection and/or treatment of diseases involving genetic mutations, particularly those diseases relating to aging, wherein the probability of having the disease increases with the age of the patient. The invention contemplates detection and/or treatment of those age related diseases which are due to mutations occurring in the DNA of somatic cells. If the mutations are not corrected, the disease may result.
Another object of the invention is to treat diseases identified according to the invention, by providing to a patient afflicted with the disease or having a propensity to develop the disease, a corrective agent such as an enzyme or oligonucleotide.
Yet another object of the invention is to provide a method for identifying age-related diseases by correlating nucleotide sequence mutation hotspots with the disease.
Other objects of the invention relate to identification, detection and treatment of age related diseases including cancers (especially non-hereditary cancers) and neurodegenerative diseases, such as Alzhemier's Disease (AD), Parkinson's Disease (PD), Down's syndrome, frontal lobe dementia (Pick's Disease), progressive supranuclear palsy (PSP), amyotrophic lateral sclerosis, Huntington's Disease, multiple sclerosis, and other degenerative diseases. Early disease diagnosis is important for effective treatment.
Alzheimer's Disease is in most cases a disease which is related to aging. AD is characterised by atrophy of nerve cells in the cerebral cortex, subcortical areas, and hippocampus and the presence of plaques, dystrophic neurites and neurofibrillary tangles. In most cases, it is not known whether AD is caused by a genetically inherited trait or by environmental factors, e.g., somatic mutations, or both. The pathogenic mutation is unknown.
Another object of the invention is to provide a diagnostic test for AD which enables definitive diagnosis of AD in living patients. Furthermore, as AD is a progressive disease, it is desirable to diagnose AD as early as possible so that preventative action may be taken.
A number of diagnostic methods have been previously suggested for AD diagnosis, most of which have focused on the amyloid protein. See for example U.S. Pat. Nos. 4,666,829, 4,816,416 and 4,933,159. However, amyloid deposits have been found in individuals, especially aged persons, who have not shown signs of dementia (See J. Biol. Chem., 265, pp 15977, 1990; and Tables 2 and 3). Diagnostic tests based on the amyloid protein have therefore been shown to lack specificity for AD.
In U.S. Pat. No. 4,727,041 a diagnostic test for AD is described based on measuring levels of somatotropin and somatomedin-C in blood sera following administration of an L-dopa proactive test.
In International patent application WO 94/02851, a method is described for identifying AD by the use of antibodies having affinity for paired helical filaments in order to determine the levels of paired helical filaments in cerebral spinal fluid. The presence of paired helical filaments is alleged to be indicative of AD.
Other diagnostic methods are based on the identification of "disease specific marker proteins" in the cerebral spinal fluid. In International patent application WO 95/05604, for example, five disease specific proteins are identified by their molecular weights. However, the specific identity of the proteins is unknown and their specific relationship to the pathogenesis of AD is also unknown. The five "disease specific marker proteins" may therefore be present as a result of a more fundamental cellular or biochemical change.
Another object of the invention is to provide for detection of AD preferably early on in the disease state. It is desirable to detect a protein or substance which is either directly responsible for the disease or is involved early on in the pathogenesis of the disease, or if not involved is nevertheless generated directly or indirectly by the mechanism causing the disease. Such a protein or substance may be the "causative" agent to the disease or may be "associated with" the disease state in the sense of being diagnostic of the disease state.
Recently, Sherrington et al. in Nature, 375, pp 254-260, 1995, identified a gene on chromosome 14 bearing missense mutations which are associated with up to 70% of familial early onset AD cases. A missense mutation involves a nucleotide substitution, usually a single nucleotide substitution, which results in an amino acid substitution at the corresponding codon. The missense mutations disclosed in Sherrington et al. are predicted to change the encoded amino acid at the following positions (numbering from the first putative initiation codon) Met to Leu at codon 146, His to Arg at codon 163, Ala to Glu at codon 246, Leu to Val at codon 286, Cys to Tyr at codon 410. It has been proposed that these mutations may be useful in identifying early onset AD. As stated earlier, the majority of AD cases are late onset (after 65 years of age; Table 1) and it is therefore still a problem to identify the majority of individuals having AD, particularly late onset AD.
Presently, there are a number of substances which are alleged to be useful in the treatment of AD. However, so far only limited success has been achieved with these substances. Methods for effectively treating and/or preventing AD are still required (see Allen and Burns, Journal of Psychopharmacology, 9, pp 43-56, 1995).